Skip to main content
2025 PharmSci 360 Main banner
Icon Legend
This session is not in your schedule.
This session is in your schedule. Click again to remove it.

Formulation and Delivery - Chemical

(W1030-06-36) Engineered Oral Nanoparticle Delivery for Metronomic Chemotherapy in a PTX-Resistant Ovarian Cancer Mouse Model: Investigating the Efficacy and Off-target Effects

Wednesday, November 12, 2025
10:30 AM - 11:30 AM CT
Purpose: Paclitaxel (PTX) is a widely used chemotherapeutic agent for treating ovarian, breast, and lung cancers [1]. Although PTX exhibits anti-angiogenic activity [2], its therapeutic potential can be optimized through metronomic chemotherapy (MET), the administration of low doses at regular intervals without extended drug-free periods. Oral delivery is critical for MET implementation, enhancing patient compliance; however, PTX’s oral bioavailability is severely limited by poor solubility, P-glycoprotein (Pgp)-mediated efflux, and extensive first-pass metabolism [3]. To overcome these barriers, we developed a receptor-mediated oral delivery strategy utilizing biodegradable polymeric nanoparticles, both undecorated (P2Ns-PTX) and decorated with gambogic acid (GA) ligand (P2Ns-GA-PTX). The purpose of this study was to evaluate shelf stability according to the international council for harmonization (ICH) guidelines for room temperature (RT) and refrigerated (RF) storage conditions, assess the efficacy of oral PTX in a PTX-resistant ovarian cancer model, and evaluate its on- and off-target effects.

Methods: The PLA-PEG based polymer (P2s) was synthesized using a polycondensation reaction and conjugated with GA forming P2s-GA [4]. The ligand GA has strong affinity toward transferrin receptor present abundantly in intestine, thus facilitates non-competitive active transport through the intestine. The nanoformulations based on this polymer (P2Ns-PTX and P2Ns-GA-PTX) were formulated using oil-in-water (o/w) emulsification method. Accelerated stability study was carried out for six months in an environmental test chamber in two conditions (at RT conditions– 400C±20C, 75%±5% relative humidity (RH) and RF conditions - 250C±20C,60%±5% RH). Every month the vials (n=3) were taken and physical appearance, particle size, shape, zeta potential and drug content were assessed. Moving forward, an orthotopic ovarian cancer was developed in female athymic nude mice by intraperitoneal injection of SKOV3-TR cells to study the efficacy of nanoformulations (P2Ns-PTX and P2Ns-GA-PTX). The mice were divided into five groups (n=12/group) (a) Healthy, (b) Untreated, (c) P2Ns-PTX(MET/oral), (d) P2Ns-GA-PTX(MET/oral) and (e) Abraxane(MTD/IP). The treatment was initiated after 2 weeks of tumor induction. The animals received 3mg/kg daily for the first week and switched to 7 mg/kg administered three times a week for the MET/oral groups (P2Ns-PTX(MET/oral) and P2Ns-GA-PTX(MET/oral)), while a single weekly dose of 21 mg/kg was given to the Maximum Tolerated Dose/Intraperitoneal (MTD/IP) (Abraxane(MTD/IP)) group. The animals were sacrificed after 51 days of treatment. The peripheral blood was analyzed to determine the effect of treatments on circulating endothelial progenitors (CEPs) [5]. Gene expression analysis was carried out for estimating the neuropathy markers to assess the effect of oral MET with PTX on peripheral neuropathy in this ovarian cancer model.

Results: The nanoparticles depicted stability under the accelerated testing conditions. The particle size, shape and drug content after six months remained almost same as compared with the first month (Figure 1). The efficacy results depicted that the untreated group had tumors in the peritoneal region with metastasis to the liver. In comparison with untreated, Abraxane(MTD/IP) depicted strong reduction in the tumor growth with similar activity observed in the P2Ns-GA-PTX(MET/oral). Even though the P2Ns-PTX(MET/oral) showed some activity, it’s not as effective as P2Ns-GA-PTX(MET/oral) (as indicated by black arrows in Figure 2a). From the survival table (Figure 2b), the Abraxane(MTD/IP) has highest survival followed by P2Ns-GA-PTX(MET/oral). The untreated group showed an increase in the percentage of CEPs compared to healthy group (****p < 0.0001). The P2Ns-GA-PTX(MET/oral) decreased the percent of CEPs (*p < 0.05) in comparison with untreated group (Figure 2c). This data provides an initial foundation to explore the anti-angiogenic activity of the oral nanoparticles in MET regimens. Peripheral neuropathy, a major off-target effect of PTX, was evaluated by measuring mRNA levels of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and Mixed lineage kinase domain-like protein (MLKL) in spinal cord and Interleukin-6 (IL-6) in brain. In spinal cord, Abraxane(MTD/IP) (** p< 0.001) treated animals showed the activation of necroptosis pathway which is evident by significant increase in RIPK3. Whereas MET/oral groups doesn’t show much significance in initiating necroptosis which might alleviate neuropathic pain. Similarly, Abraxane(MTD/IP) and P2Ns-PTX(MET/oral) (* p< 0.05) exhibited promising increase in MLKL expression which is reduced in P2Ns-GA-PTX(MET/oral) (Figure 3a and 3b). Elevated mRNA levels of IL-6, an inflammatory marker in brain suggest neuroinflammation in Abraxane(MTD/IP) treated animals (**** p< 0.0001) and in P2Ns-PTX(MET/oral) (** p< 0.001), which is decreased in the P2Ns-GA-PTX(MET/oral) (Figure 3c).

Conclusion: P2Ns-GA-PTX and P2Ns-PTX demonstrated acceptable stability under ICH-accelerated conditions. Preliminary findings indicate effective anti-angiogenic activity and a protective effect against PTX-induced peripheral neuropathy in a PTX-resistant ovarian cancer model. Ongoing studies aim to further elucidate the mechanisms underlying the observed anti-cancer and neuroprotective effects of these nanoparticle formulations.

References: 1. Sharifi-Rad, Javad et al. “Paclitaxel: Application in Modern Oncology and Nanomedicine-Based Cancer Therapy.” Oxidative medicine and cellular longevity vol. 2021 3687700. 18 Oct. 2021, doi:10.1155/2021/3687700
2. Bocci, Guido et al. “The Pharmacological Bases Of the Antiangiogenic Activity of Paclitaxel.” Angiogenesis vol. 16,3 (2013): 481-92. doi:10.1007/s10456-013-9334-0
3. Sparreboom, A et al. “Limited Oral Bioavailability and Active Epithelial Excretion of Paclitaxel (Taxol) caused by P-glycoprotein in the Intestine.” Proceedings of the National Academy of Sciences of the United States of America vol. 94,5 (1997): 2031-5. doi:10.1073/pnas.94.5.2031
4. Ganugula, Raghu et al. “Next Generation Precision-Polyesters Enabling Optimization of Ligand-Receptor Stoichiometry for Modular Drug Delivery.” Journal of the American Chemical Society vol. 139,21 (2017): 7203-7216. doi:10.1021/jacs.6b13231
5. Kamat, Aparna A et al. “Metronomic Chemotherapy Enhances the Efficacy of Antivascular Therapy in Ovarian Cancer.” Cancer research vol. 67,1 (2007): 281-8. doi:10.1158/0008-5472.CAN-06-3282

Acknowledgements: This work is funded by The University of Alabama initial seed grant.


Figure 1. Accelerated stability study performed as per the ICH guidelines (at RT conditions– 400C±20C, 75%±5% RH and RF conditions - 250C±20C,60%±5% RH). Data depicting the intactness of the cake, Scanning electron microscope (SEM) micrographs, drug content of P2Ns-PTX and P2Ns-GA-PTX from month 1 through month 6.


Figure 2. Anatomic images depicting the effect of treatments in orthotopic ovarian cancer induced by SKOV3-TR cell injection in the peritoneal region of NU/J mice. Images (a) showing the tumors in the mice, (b) survival summary of the study and (c) flow cytometry analysis of circulating endothelial progenitors (CEPs). The animals in P2Ns-PTX(MET/oral) and P2Ns-GA-PTX(MET/oral) received 3mg/kg daily for the first week and switched to 7 mg/kg thrice weekly for the rest of the study. Statistical analysis was performed using one-way ANOVA. Significant values were compared with the untreated group: *, P < 0.05.


Figure 3. Real time PCR data depicting the mRNA levels of (a) RIPK3 and (b) MLKL in spinal cord and (c) IL-6 in brain. Statistical analysis was performed using one-way ANOVA. Significant values were compared with the untreated group: *, P < 0.05; **, P < 0.01; and ****, P<0.0001.